Methods of preparing cytotoxic benzodiazepine derivatives

Patent metadata

Field	Value
Publication number	US-10844078-B2
Application number	US-201916442718-A
Country	US
Kind code	B2
Filing date	Jun 17, 2019
Priority date	Jan 25, 2017
Publication date	Nov 24, 2020
Grant date	Nov 24, 2020

Abstract

The invention provides novel methods for preparing indolinobenzodiazepine dimer compounds and their synthetic precursors.

First claim

The invention claimed is:

1. A method of preparing a compound of formula (II),

comprising reacting a compound of formula (I):

with hydrochloric acid in toluene, wherein the hydrochloric acid is 30-38 w/w % of hydrochloric acid in water, and wherein the compound of formula (II) is purified by crystallization by cooling a concentrated solution of the compound in toluene.

2. A method of preparing a compound of formula (IV-1):

or a salt thereof, comprising the steps of:
1) reacting a compound of formula (I):

with hydrochloric acid in toluene to form a compound of formula (II), wherein the hydrochloric acid is 30-38 w/w % of hydrochloric acid in water:

and
wherein the compound of formula (II) is purified by crystallization by cooling a concentrated solution of the compound in toluene;
2) reacting the compound of formula (II) with a monomer compound of formula (a) in the presence of an alcohol activating agent and an azodicarboxylate,

to form a compound of formula (III):

or a salt thereof, wherein the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine, and wherein the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD);
3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b) in the presence of a base:

to form the compound of formula (IV-1) or a salt thereof, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride.

3. A method of preparing a compound of formula (A-1):

or a salt thereof, comprising the steps of:
1) reacting a compound of formula (I):

with hydrochloric acid in toluene to form a compound of formula (II), wherein the hydrochloric acid is 30-38 w/w % of hydrochloric acid in water:

and
wherein the compound of formula (II) is purified by crystallization by cooling a concentrated solution of the compound in toluene;
2) reacting the compound of formula (II) with a monomer compound of formula (a) in the presence of an alcohol activating agent and an azodicarboxylate,

to form a compound of formula (III):

or a salt thereof, wherein the alcohol activating agent is a trialkylphosphine, triarylphosphine, or triheteroarylphosphine, and wherein the azodicarboxylate is selected from the group consisting of: diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), 1,1′-(azodicarbonyl)dipiperidine (ADDP), and ditertbutyl azodicarboxylate (DTAD);
3) reacting the compound of formula (III) or a salt thereof with a monomer compound of formula (b) in the presence of a base:

to form a compound of formula (IV-1):

or a salt thereof, wherein the base is sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, or potassium hydride;
4) reacting the compound of formula (IV-1) or a salt thereof with a reducing agent to form a compound of formula (V-1):

or a salt thereof; and
5) reacting the compound of formula (V-1) or a salt thereof, with a compound of formula (X-1):

to form the compound of formula (A-1) or a salt thereof, wherein E is OH, halide or —C(═O)E is an activated ester.

4. The method of claim 1 , wherein the reaction between the compound of formula (I) and hydrochloric acid is carried out at a temperature between 40° C. and 105° C.

5. The method of claim 4 , wherein the reaction is carried out at a temperature between 90° C. and 100° C.

6. The method of claim 2 , wherein the alcohol activating agent is triphenylphosphine and the azodicarboxylate is diisopropyl azodicarboxylate (DIAD).

7. The method of claim 2 , wherein the reaction of step 2) comprises the steps of i) mixing the alcohol activating agent and the azodicarboxylate to form an alcohol activating agent-azodicarboxylate complex; ii) reacting the compound of formula (II) with the alcohol activating agent-azodicarboxylate complex to form a mixture of the compound of formula (II) and the alcohol activating agent-azodicarboxylate complex; and iii) reacting the mixture of step ii) with the monomer compound of formula (a).

8. The method of claim 2 , wherein in step 3), the base is potassium carbonate.

9. The method of claim 8 , wherein in step 3), the reaction between the compound of formula (III) or a salt thereof and the monomer compound of formula (b) is carried out in the presence of potassium iodide.

10. The method of claim 3 , wherein in step 4), the reducing agent is Fe/NH 4 Cl.

11. The method of claim 3 , wherein the compound of formula (X-1) is represented by formula (X-1a):

and the compound of formula (X-1a) or a salt thereof is prepared by a method comprising the steps of:
a) reacting a compound of formula (VI):

or a salt thereof, with a compound of formula (d) in the presence of an activating agent:

or a salt thereof, to form a compound of formula (VII):

or a salt thereof;
b) reacting the compound of formula (VII) or a salt thereof with a carboxylic acid deprotecting agent to form a compound of formula (VIIIa):

or a salt thereof;
c) reacting the compound of formula (VIIIa) or a salt thereof with a compound of formula (c-1) in the presence of an activating agent:

Assignees

• Immunogen Inc

Inventors

• Gérard Baudouin
• Silva Richard A
• Miller Michael Louis
• Shizuka Manami

Classifications

• C07D519/04

  Dimeric indole alkaloids, e.g. vincaleucoblastine · CPC title

• C07D519/00 Primary

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D207/452

  with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom · CPC title

• C07C205/19 Primary

  having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms · CPC title